The antibiotic rifaximin was originally disclosed in Italy as IT Patent 1154655. The related U.S. Pat. No. 4,341,785 to Marchi et al. discloses imidazo-rifamicyn derivatives having antibacterial utility, and the related process for preparing it. The US '785 patent also discloses a pharmaceutical antibacterial composition and a method of using it to treat antibacterial diseases of the gastrointestinal tract (GIT).
Rifaximin is essentially a low-solubility, non-absorbable, non-systemic, semi-synthetic antibiotic, related to rifamycin. The antimicrobial spectrum (in vitro) includes most gram-positive and gram-negative bacteria; and both aerobes and anaerobes. Rifaximin is approved in certain countries for the treatment of pathologies whose etiology is in part or totally due to intestinal acute and chronic infections sustained by gram-positive and gram-negative bacteria, with diarrhea syndromes, altered intestinal microbial flora, summer diarrhea-like episodes, traveler's diarrhea and enterocolitis; pre- and post- surgery prophylaxis of the infective complications in gastro intestinal surgery; and hyperammonaemia therapy as coadjutant. The drug has been found to have no significant side effects.
Rifaximin is currently marketed as tablets at the dosage of 200 mg for traveller's diarrhea under the brand name “Xifaxan®”.
The most common dosage forms currently employed for oral administration of active substances are tablets and capsules. However, in recent years awareness of the drawbacks of using these dosage forms has increased. Thus, tablets and capsules are generally less suitable for administering of an active substance to pediatric and geriatric patients for whom tablets or capsules are difficult to ingest, or the large dosages necessitate the administration of several tablets or capsules at a time, resulting in impaired patient compliance.
In such situations, oral liquid dosage forms are the preferred choice. However, these dosage forms usually lead to perceptible exposure of the active drug ingredient to the taste buds, which is a very serious problem when the drug has an unpleasant or bitter taste.
The unpleasant or bitter taste of the drugs, which are orally administered, is disadvantageous in several aspects. Taste is an important parameter governing the compliance. The disagreeable and unpleasant taste of drugs causes difficulties in swallowing or causes patients to avoid their medication, thereby resulting in low patient compliance. Thus, taste-masking technologies are considered important and are developed by many researchers.
Another problem associated with an active to be formulated in a liquid dosage form is its low solubility which further affects the dissolution, potency of the drug and onset time, the potency and onset time depends on the dissolution rate of the drug.
Liquid dosage forms may be formulated as powders or granules to be reconstituted before administration, powders or granules to be admixed with a liquid in a container such as a glass before administration, thereby overcoming the difficulties involved in administering an active substance in tablet or capsule form. However, with such a formulation other problems arise, especially when the active substance in question is not dissolved in the liquid, but is present in particulate form. In such cases, the particles tend to sink to the bottom of the glass and stay there even when the contents of the glass are stirred before the glass is upended for ingestion of the liquid or to adhere to the sides of the glass when the liquid is ingested. In this way a certain amount of the active substance will remain in the glass giving rise to an unacceptable variation in the dosage of the active substance actually ingested by those to whom it is administered in this form. Furthermore, such granules or particles often have an unpleasant feel in the mouth as they typically have an irregular shape which makes them feel gritty, and they also tend to adhere to oral mucosa after the liquid carrier has been washed down. Such a dosage form therefore also tends to lead to reduced patient compliance.
CN1485034A describes rifaximin suspension which has granules for reconstitution with good taste.
The reconstitutable granules for suspension have many disadvantages such as reduced patient compliance and further there are chances for dose variation and stability problems.
In light of the above disadvantages, still there is a need to develop rifaximin suspension which can overcome the above disadvantages.
We have now found that rifaximin can be formulated in the form of ready-to-use suspension, with an improved taste, stability and solubility by careful manipulation of the flavouring agent, sweetening agent and particle size. Such formulations are envisaged to fulfill the existing need of patient friendly dosage forms especially for the pediatric and geriatric patient populations. Further, this ready-to-use suspension has many advantages over the reconstituted granules for suspension that it has improved patient compliance, improved stability and there is no dose variation while administration of ready-to-use suspension.